JPS6133807B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a composition for producing a ^99m technetium-radiodiagnostic agent for scintigraphy of bone and calcific tumors.

It has long been known that X-ray examinations, especially for the early diagnosis of skeletal diseases and tumors, are still an effective means, but they are not entirely satisfactory. New methods have therefore been developed that use the radioisotopes fluorine-18 and strontium-85, which are selectively absorbed within the skeleton, in particular within diseased areas. This radioactive isotope is also increased in calcareous tumors. Radiography therefore allows this skeletal or tissue disease to be recognized and located. However, the production of ¹⁸ F requires complex equipment not available in hospitals, and furthermore, ¹⁸ F has an extremely short half-life time of only 110 minutes. ⁸⁵ Sr, on the other hand, has a very long half-life of 65 days and, due to its low disintegrability, requires very long scanning times.

Based on this drawback, interest has recently been focused on technetium-99m, an isotope with a half-life of 6 hours. For its production, an easy-to-handle device is provided which allows the radioactive isotope to be obtained in the form of ^99m pertechnetate by elution with isotonic saline solution.

Pertechnetate-99m binds ^non -specifically to skeletal or calcareous tumors in the body.
⁸⁵ Different from Sr ²⁺ . Therefore, for its use,
It should be cyclized to a lower oxidation stage and then stabilized at that oxidation stage using a suitable complex formation. The complex should also have a high selectivity with respect to good absorption in skeletal or calcareous tumors. However, first results were obtained using polyphosphates of low valence and whose complexes are characterized by moderate stability. Furthermore, by mixing ^{the 99m} pertechnetate solution with an aqueous solution of ditin()ethane-1-hydroxy-1,1-diphosphonate, a usable drug was prepared, which has been described in the literature (J. Nucl.Med. vol. 14, p. 73, J.
(Refer to Nucl. Med. Vol. 13, p. 947). However, the stability of this ditin()ethane-1-hydroxy-1,1-diphosphonate solution is affected by the excess ethane-1-
Limitations were also found with hydroxy-1.1-diphosphonates, in particular as a result of the tendency to hydrolyze tin() ions.

By the way, certain aminophosphonic acids and their salts are preferred due to the high stability of their complexes with low technetium ions and the high stability of ^99m Tc deposition in skeletal tissues and in calcareous tumors. There was found.

The task of producing a soluble and stable product that, after addition to a pertechnetate solution, is an effective and selective diagnostic agent for radiography of skeletal and calcareous tumors consists of a mixture of the following components: Solved by composition: (a) General formula one or more aminophosphonic acids or a pharmaceutically usable water-soluble salt thereof; and (b) a stoichiometrically lower amount of pharmaceutically usable tin()-, iron(()) relative to (a). )-or chromium ()-salt.

With this diagnostic agent it is possible to easily produce highly stable products which are conveniently supplied in solid form as tablets or in solution form contained in ampoules. The contents of the tablet or ampoule, after addition to the pertechnetate solution, form a highly effective diagnostic agent for the diagnosis of bone tumors, local disorders of bone substance metabolism as well as calcified tissue tumors.

For pharmaceutical uses, in place of or in combination with the aminophosphonic acids, pharmaceutically acceptable salts thereof, such as sodium-, potassium-, magnesium-, zinc-, ammonium-, and substituted ammonium salts, such as , mono-, di- or triethanolammonium salts, in which only a portion of the acidic protons are replaced by other cations, as well as partial salts and complete salts, can be used; Partial salts of 9) are preferred. Mixtures of the aforementioned salts can likewise be used.

Regarding the stabilization of ^99m Tc- ions in complexes and the elimination of colloidal particle formation, ^99m in skeletal or calcified tumors
Particularly good results regarding the selectivity of the deposition of ^mTc are
Obtained with the following preferred sodium partial salts of aminophosphonic acids: 1 2-Hydroxy-2,7-dioxo-3-amino-3-phosphono-1,2-azaphosphacycloheptane, disodium salt 2 Azacyclo Heptane-2.2-diphosphonic acid, disodium salt 3 3-Amino-1-hydroxypropane-1.
1-diphosphonic acid, disodium salt.

The preferred aminophosphonic acid partial salts exhibit excellent absorption by the skeleton and very little absorption into soft tissues other than calcified tumors. These are highly suitable for examining bone metastases of breast or prostate cancer.

Aminophosphonic acids of the formula ( ) can be obtained by the reaction of a short-chain substituted or unsubstituted dicarboxylic acid diamine, α· _ω -dinitrile or _e.g. It can be produced by subsequent acidic hydrolysis.

Azacycloalkane-2,2-diphosphonic acids of the formula ( ) can advantageously be prepared by reaction of a lactam with a phosphonylating agent such as a phosphorus halide ( ) or H ₃ PO ₃ .

3-Amino-1 _- hydroxypropane-1,1-diphosphonic acid of _the formula It can be manufactured by

The phosphonic acids can be converted into the desired salts by complete or partial neutralization in known manner.

Tin()-, iron()- and chromium()-salts with pharmaceutically acceptable anions are added as reducing agents. As a result of its generally accepted safety,
Chlorides and sulfates are preferred, especially tin chloride () due to their high reducing ability and absence of water of crystallization.
is advantageous.

This additive serves to recycle ^{the 99m} pertechnetate effluent from commercial ^99m pertechnetate generators. The resulting reducing, low-value ^99m Tc-ions can then be complexed by the aminophosphonic acid-complexing agent and transported within the tissue to the skeleton or calcareous tumors.

Aqueous solution of the above aminophosphonic acid and tin ()
-, iron ()- or chromium ()- salts have the undesirable property of oxidizing or hydrolyzing over long periods of time in the presence of air. This difficulty can be avoided by enclosing the solution in ampoules under nitrogen or by using the composition according to the invention in the form of tablets or dragees. Therefore, the composition according to the invention
Handled and stored in a stable form, the ^99m pertechnetate solution can only be supplied immediately before the intended use. In this case, an excellent diagnostic agent for bone and tumor radiography is obtained, which produces pronounced scintillation images at the lowest absorption of metal ions.

The desired ^99m Tc activity is very low, approximately 10-15 mCi, and the amount of tin () required when using aminophosphonic acids is likewise very low. However, an advantageous amount is greater than the stoichiometric amount required for the reduction of ^99m pertechnetate, and together with a significantly larger amount of aminophosphonate, stabilized with an excess of aminophosphonate.
^99m Tc-Sn-aminophosphonate-complex, the exact structure of which is unknown.

A reducing agent is added to the composition of the present invention in an amount of 1% per composition.
Advantageously, it is added in an amount of ~5% by weight.

For the handling and metering of small quantities of the necessary reducing complex-forming compositions, it is advantageous to use pharmaceutically acceptable fillers, such as glucose or sodium chloride. Particular preference is given here to sodium chloride. This is because it also contributes to the maintenance of isotonic pressure during the sometimes necessary dilution of the pertechnetate solution with sterile water.

The active ingredients of this composition are mixed homogeneously and filled in solid form into standard glass ampoules or compressed into tablets using glucose and/or sodium chloride as fillers. However, it is advantageous to prepare a solution of the components, transfer this under nitrogen into standard ampoules and lyophilize. This lyophilizate can be stored under nitrogen or in vacuum. Optionally, isotonic aqueous solutions of the components can be stored under nitrogen.

Example (A) Composition of ingredients (1) In a graduated 10ml standard ampoule,
An aqueous solution of 8 mg of 2-hydroxy-2,7-dioxo-3-amino-3-phosphono-1,2-azaphospha-cycloheptane-disodium salt and 0.15 mg of anhydrous tin chloride () are charged. The solution is lyophilized and the ampoule sealed under vacuum or filled with nitrogen.

For use, this substance mixture is dissolved in 5 ml of sterile isotonic ^99m pertechnetate solution and injected intravenously.

2 A graduated standard-glass ampoule is filled with an aqueous solution of 8 mg of azacycloheptane-2,2-diphosphonic acid-disodium salt and 0.10 mg of chromium chloride (). The solution is lyophilized and the ampoule sealed under vacuum or filled with nitrogen.

For use, this substance mixture is dissolved in 5 ml of sterile isotonic saline solution and injected after mixing with isotonic ^99m pertechnetate solution.

3 Fill a graduated 5 ml standard ampoule with 8 mg of 3-amino-1-hydroxypropane-1,1-diphosphonic acid disodium salt and 0.15 mg of iron sulfate ().

For use, this substance mixture is dissolved in 5 ml of sterile isotonic saline solution and injected after mixing with isotonic ^99m pertechnetate solution.

4 Fill a graduated 10 ml standard ampoule with 8 mg of 3-amino-1-hydroxypropane-1,1-diphosphonic acid disodium salt and 0.15 mg of tin chloride dissolved in 5 ml of sterile isotonic saline solution. do.

5 Azacycloheptane-2,2-diphosphonic acid-disodium salt 8 mg, tin chloride () 0.2
mg, sodium chloride 45 mg and glucose 26.8
mg is compressed into small tablets weighing 80 mg. The tablet dissolves rapidly in 5 ml of sterile water, producing an isotonic solution.

6 Azacycloheptane-2,2-diphosphonic acid-disodium salt 4 mg, 3-amino-1-
Hydroxypropane-1,1-diphosphonic acid-disodium salt 4 mg, iron sulfate () 0.2
mg, sodium chloride 45 mg and glucose 26.8
mg is compressed into small tablets weighing 80 mg. The tablet dissolves rapidly in 5 ml of sterile water, producing an isotonic solution.

7 2-hydroxy-2,7-dioxo-3-
8 mg of amino-3-phosphono-1,2-azaphosphacycloheptane-disodium salt, 0.07 mg of tin chloride (), and 0.08 mg of iron sulfate () were dissolved in 5 ml of sterile isotonic saline and placed in a 5 ml standard ampoule. Fill.

(B) Approximately 50 mCi/ml activity from each composition in dissolved form.
After addition of about 5 ml of ^99M pertechnetate solution and careful shaking, a diagnostic agent is obtained which can be administered to humans, for example by intravenous injection. Weight approximately 70Kg
For skeletal scintigraphy in adults, approximately 1 ml of the solution can be used and injected gradually, and in children a correspondingly smaller amount can be used. For scintigraphy of calcified soft tissues, for example calcified tumors, or in the case of advanced calcific atherosclerosis, higher amounts can optionally be used. Injection 1 after manufacture
Advantageously, it is carried out for ~2 hours.

(C) The diagnostic agent prepared from the mixture according to Example (A) 3 is:
Excellent results were shown during skeletal scintigraphy. It is particularly effective in the examination of bone metastases in patients with breast or prostate cancer, making it an ideal complement to radiographic diagnosis.

In rats, the good human specimen for this study, the results of partition studies at 0.01-1.0 mCi of ^99m Tc indicate that approximately 60-70% of the dose is It is clear that it goes to the skeleton. In the blood, 5% of the activity is still found after 3 hours, and this remainder is eliminated with the urine. This distribution is considered favorable.

The optimal time for scintigraphic diagnosis is approximately 3 hours after injection. For scintigraphy of calcified soft tissue, such as tumors, muscle tissue or progressive calcified atherosclerosis, different times after injection are optimal. This time is
It depends on the local blood perfusion (blood purification rate) of the tissue in question.

Claims (1)

[Scope of Claims] 1. A composition for producing a ^99m technetium radiodiagnostic agent for scintigraphy of bone and calcific tumors, which comprises (a) the general formula one or more aminophosphonic acids or a pharmaceutically usable water-soluble salt thereof; and (b) a stoichiometrically small amount of pharmaceutically usable tin()-, iron relative to component (a). 1. A composition for producing a ^99m technetium radiodiagnostic agent, characterized in that it contains a mixture of ()- or chromium ()-salt. 2. The composition according to claim 1, wherein the component (b) is 1 to 5% by weight based on the total components. 3. The composition according to claim 1 or 2, wherein the PH-value of the composition is within the range of 5 to 9. 4 Claims 1 to 3 containing 2-hydroxy-2,7-dioxo-3-amino-3-phosphone-1,2-azaphosphacycloheptane in the form of disodium salt The composition according to any one of the items. 5. The composition according to any one of claims 1 to 3, which contains azacycloheptane-2,2-diphosphonic acid in the form of a disodium salt. 6 3-amino-1-hydroxypropane-1.
4. A composition according to any one of claims 1 to 3, containing 1-diphosphonic acid in the form of its disodium salt.